Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study
Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study
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DOI：
10.1016/s1470-2045(21)00274-6
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发表时间：
2021-07-30
期刊：
影响因子：
51.1
通讯作者：
Eiber, Matthias
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文献类型：
--
作者：
Gafita, Andrei;Calais, Jeremie;Eiber, Matthias
背景镥 177 (Lu-177) 前列腺特异性膜抗原 (Lu-177-PSMA) 是一种针对转移性去势抵抗性前列腺癌 (mCRPC) 患者的新型靶向治疗方法。 Lu-177-PSMA 加强其临床实施后的结果预测因素尚未确定。我们的目的是开发列线图来预测 mCRPC 患者接受 Lu-177-PSMA 治疗后的结果。方法 在这项多中心回顾性研究中，我们筛选了在 2014 年 12 月 10 日至 2019 年 7 月 19 日期间接受 Lu-177-PSMA 治疗的 mCRPC 患者，作为之前 2 期试验的一部分 (NCT03042312， ACTRN12615000912583）或德国、美国和澳大利亚六家医院和学术中心的同情访问计划。符合条件的患者每 6-8 周接受一次静脉注射 6.0-8.5 GBq Lu-177-PSMA，最多四到六个周期，并具有可用的基线 [Ga-68]Ga-PSMA-11 PET/CT 扫描、临床数据和生存结果。假定的预测因子包括 18 个治疗前临床病理学和 [Ga-68]Ga-PSMA-11 PET/CT 变量。数据在本地收集并集中。列线图的主要结果是总生存期和前列腺特异性抗原（PSA）无进展生存期。每个结果的列线图是根据 Cox 回归模型计算的，并带有用于变量选择的 LASSO 惩罚。模型性能通过检查歧视性（Harrell 的 C 指数）、校准（校准图）和效用（患者分层为低风险组与高风险组）来衡量。使用引导程序对模型进行内部验证，并通过计算其在验证队列中的表现进行外部验证。结果在 2019 年 4 月 23 日至 2020 年 1 月 13 日期间，对 414 名患者进行了筛查；其中 270 名 (65%) 人符合资格，并被分为开发组 (n=196) 和验证组 (n=74)。中位随访时间为 21.5 个月 (IQR 13.3-30.7)。列线图中包含的预测因子包括前列腺癌初次诊断后的时间、化疗状态、基线血红蛋白浓度和 [Ga-68]Ga-PSMA-11 PET/CT 参数（分子成像 TNM 分类和肿瘤负荷）。总体生存模型的 C 指数为 0.71 (95% CI 0.69-0.73)。在内部验证 (0.71 [0.69-0.73]) 和外部验证 (0.72 [0.68-0.76]) 中获得了类似的 C 指数。 PSA 无进展生存模型的 C 指数为 0.70 (95% CI 0.68-0.72)。在内部验证 (0.70 [0.68-0.72]) 和外部验证 (0.71 [0.68-0.74]) 中获得了类似的 C 指数。两个模型都经过充分校准，并且它们的预测与观察到的结果相关。与高风险患者相比，低风险患者在验证队列中的总生存期显着更长（24.9 个月 [95% CI 16.8-27.3] vs 7.4 个月 [4.0-10.8]；p
Background Lutetium-177 (Lu-177) prostate-specific membrane antigen (Lu-177-PSMA) is a novel targeted treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Predictors of outcomes after Lu-177-PSMA to enhance its clinical implementation are yet to be identified. We aimed to develop nomograms to predict outcomes after Lu-177-PSMA in patients with mCRPC.Methods In this multicentre, retrospective study, we screened patients with mCRPC who had received Lu-177-PSMA between Dec 10, 2014, and July 19, 2019, as part of the previous phase 2 trials (NCT03042312, ACTRN12615000912583) or compassionate access programmes at six hospitals and academic centres in Germany, the USA, and Australia. Eligible patients had received intravenous 6.0-8.5 GBq Lu-177-PSMA once every 6-8 weeks, for a maximum of four to six cycles, and had available baseline [Ga-68]Ga-PSMA-11 PET/CT scan, clinical data, and survival outcomes. Putative predictors included 18 pretherapeutic clinicopathological and [Ga-68]Ga-PSMA-11 PET/CT variables. Data were collected locally and centralised. Primary outcomes for the nomograms were overall survival and prostate-specific antigen (PSA)-progression-free survival. Nomograms for each outcome were computed from Cox regression models with LASSO penalty for variable selection. Model performance was measured by examining discrimination (Harrell's C-index), calibration (calibration plots), and utility (patient stratification into low-risk vs high-risk groups). Models were validated internally using bootstrapping and externally by calculating their performance on a validation cohort.Findings Between April 23, 2019, and Jan 13, 2020, 414 patients were screened; 270 (65%) of whom were eligible and were divided into development (n=196) and validation (n=74) cohorts. The median duration of follow-up was 21.5 months (IQR 13.3-30.7). Predictors included in the nomograms were time since initial diagnosis of prostate cancer, chemotherapy status, baseline haemoglobin concentration, and [Ga-68]Ga-PSMA-11 PET/CT parameters (molecular imaging TNM classification and tumour burden). The C-index of the overall survival model was 0.71 (95% CI 0.69-0.73). Similar C-indices were achieved at internal validation (0.71 [0.69-0.73]) and external validation (0.72 [0.68-0.76]). The C-index of the PSA-progression-free survival model was 0.70 (95% CI 0.68-0.72). Similar C-indices were achieved at internal validation (0.70 [0.68-0.72]) and external validation (0.71 [0.68-0.74]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (24.9 months [95% CI 16.8-27.3] vs 7.4 months [4.0-10.8]; p